1. Field of the Invention
The present invention relates to a biodegradable copolymer, and in particular relates to the thermosensitive property of a solution thereof.
2. Description of the Related Art
For hard tissue recovery/surgery, fixation of bone fragments in a comminuted or joint fracture is one of the most challenging procedures. For fixation, a K-pin, a bone nail, or a steel wire may be utilized, however, ablation of soft tissue adhered on the bone fragments is necessary before using the fixation materials. Therefore, blood circulation and bone healing are degraded, and the bone fragments increase risk of destruction into a more powdery form. Commercially available bone cement (e.g. polymethylmethacrylate), serves as an adhesion for bone fragments or a filler for bone cavities. The biological inert bone cement rarely causes allergic reactions and cannot be absorbed by the human body, such that complete bone healing of the bone fragments fixed by the bone cement is difficult. As such, the bone cement is not suitable for fracture caused by trauma. For orthopedist, an absorbable bioadhesion material for bone fragment adhesion to improve bone healing is demanded.
For soft tissue recovery/surgery, an endoscope is utilized for minimal invasive surgery, specially in shoulder reconstructive surgery. Conventional techniques utilize drills to drill a hole through the shoulder bone to seam bone and tendons, thereby consuming time. Recently, sutureless anchors and knotless anchors have been popularly utilized to become mainstream techniques for saving operating time due to inconvenience, and further prevent abrasion and tissue reaction caused from residue knots. If the sutureless anchor is utilized for an ablated tissue, the stress of the anchor will be concentrated on the ablated tissue to form a bulge, such that the bioadhesion is utilized to adhere to the ablated tissues to accelerate tissue regeneration. If the knotless anchor is utilized for the ablated tissue, the healing effect will be dependant upon the operating skill of the surgeon, anchor strength, and degree of tissue regeneration. Meanwhile, the bioadhesion is utilized to adhere to the ablated tissues to improve the healing effect.
For a hip joint, avascular necrosis (AVN) is mainly found in youths and elderly. Although an artificial hip joint can replace a hip joint with AVN, early treatment can also be utilized to cure 75% AVN patients. The present treatment for AVN is core decompression, wherein a hole is drilled from the edge to the front end of the thighbone, and autogenic bone grafts full of veins are implanted into the drilled hole, such that blood is able to flow to the necrosis zone for bone regeneration. However, the described treatment needs an additional operation to collect the autogenic bone grafts from the patient's body, thereby extending the healing period. Note also that a combination of bioadhesion and medicine can be implanted into the thighbone to stimulate veins and bone regeneration following degradation of the bioadhesion to immediately release the medicine.
Meanwhile, delivery of biological activity factors such as medicines, cells, growth factors, and genes are important in biological medicine applications such as medicine therapy, gene therapy, and tissue engineering. The materials which serve as a delivery carrier must possess bio-compatibility and biodegrability for an implanting in vivo. In addition, the material should easily flow in vitro to evenly mix with medicine. The material which is subsequently injected into a body by a catheter or an endoscope, should transform to a gel after injection for fixing activity factors in the predetermined tissue regions, and slowly releasing the activity factors to complete treatment. Presently, a suitable delivery material is rare. Some materials form a gel through chemical reaction, thereby influencing the activity of the biological activity factors or damaging the implanted tissue region. Some materials have excellent thermosensitivity and gel formability but poor biodegradability, thereby preventing applicability for an implantation in vivo.
In U.S. Pat. No. 5,514,380, Song discloses a biodegradable copolymer gel which serves as a medicine delivery matrix. The copolymer is composed of hydrophilic and hydrophobic segments, the hydrophilic segment is primarily polyethyleneoxide (PEO), and the hydrophobic segment is polylactide (PLA), polyglycolide (PGA), polylactide-glycolide (PLGA), or polycaprolactone (PCL). The multi block copolymer is applied to a drug releasing carrier. However, the patent discloses a multi block copolymer such as ABABAB, wherein A means hydrophilic segment and B means hydrophobic segment, without disclosing the thermosensitive property. Furthermore, the patent also fails to disclose that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid.
MacroMed Corporation has four U.S. Pat. No. 5,702,717, No. 6,004,573, U.S. Pat. No. 6,117,949, and U.S. Pat. No. 6,201,072. The patents disclose biodegradable thermosensitive triblock copolymer, such as ABA or BAB. A hydrophilic segment A is a polyethylene glycol (PEG), and a hydrophobic segment B is a polyester. The biodegradable triblock copolymer has a molecular weight of 2000 to 4990 g/mol, and a reverse thermal gelation. The hydrogel, prepared from the copolymer, can be mixed with a medicine at room temperature. The mixture will transform to a gel after being injected into homoiothermic animals, and the medicine release rate is determined by the hydrolysis rate of the gel in vivo. The hydrolysis product of the gel is free of bio-toxicity. However, the patents do not disclose the thermosensitive diblock copolymer AB, and that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid.
In U.S. Pat. Nos. 6,451,346 and 6,004,573, Amgen Corporation discloses ABA and AB block copolymers with pH and thermo sensitivities. The hydrophilic segment A of the copolymer is PEG, and the hydrophilic segment B is PLA or PLGA. However, the patent does not disclose that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid. Furthermore, succinic anhydride is necessary to be a crosslinking agent between the hydrophobic and hydrophilic segments, and is different from the direct ring-opening product of the invention.
In U.S. Pat. No. 7,087,244, Byeongmoon Jeong discloses triblock copolymers such as ABA and BAB with thermosensitivity. The copolymers are applied as a biological activity factor release carrier. However, the patent does not disclose that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid, and the copolymer thereof is triblock not diblock.
In U.S. Pat. Nos. 5,410,016, 5,567,435, and 5,986,043, Hubbell discloses a diblock copolymer AB system. The initiator thereof is a photo initiator or a thermo initiator. In U.S. Pat. No. 5,410,016, the hydrophobic segment B is poly(α-hydroxy acid) (PHA), poly(glycolic acid) (PGA), PLA, or polylactone such as poly(ε-caprolactone) (PCL), poly(δ-valerolactone) (PVL), or poly(λ-butyrolactone) (PBL). However, the patent does not disclose that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid. Alternatively, in the U.S. Pat. Nos. 5,567,435, and 5,986,043, the diblock copolymer has a PEG center with extension such as PHA, PGA, PLA, polylactone, poly(amino acid), polyanhydride, poly(orthoester), poly(orthocarbonate), or poly(phosphoester). However, similarly, the patents also fail to disclose that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid. In addition, U.S. Pat. No. 6,060,582 discloses a photopolymerized diblock copolymer with three segments B, L, and P. P is an ethylene segment for photo initiation, B is PEG, and L is PHA, acrylic ester monomer or oligomer. The P segment and L segment are first coupled to form a hydrophobic segment, and the hydrophobic segment is then coupled with the B segment. Although the diblock copolymer in U.S. Pat. No. 6,060,582 can be applied for anti-adhesion after surgery, releasing medicine, tissue adhesion, and preventing cell adhesion to tissue, it still fails to disclose that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid.
In U.S. Pat. No. 5,514,380, Samyang Corporation discloses a copolymer with hydrophilic and hydrophobic segments. The hydrophilic segment is PEO and the hydrophobic segment is PLA, PGA, PLGA, or PCL. The copolymer is a thermoplastic biodegradable gel. However, the patent fails to disclose thermosensitivity, and also fails to disclose that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid.
In U.S. Pat. No. 6,136,333, Life Medical Sciences Corporation discloses block copolymers AB and ABA. Segment A is polyester, segment B is polyoxyalkylene polymer unit, segments A and B have a ratio of 1:0.1 to 1:100, and the segments A and B have hexamethylene diisocyanate (HMDI) as crosslinking agent therebetween. The block copolymers serve as anti-adhesion material. However, the patent does not disclose the thermosensitivity, and fails to disclose that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid.
In U.S. Pat. No. 6,841,617, Battle Memorial Institute discloses an An(B) block copolymer that is a thermosensitive and biodegradable gel, wherein A is PEG and B is polyester. However, the polymerization thereof is through grafting, and it also fails to disclose that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid.
In U.S. Pat. No. 7,094,810, Lapopharm Corporation discloses a block copolymer AB. The hydrophilic segment A is PEO, and an the hydrophobic segment B is poly(butyl(alkyl)acrylate-co-(alkyl)acrylic acid. However, the patent fails to disclose that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid.
In U.S. Pat. No. 7,153,520, Samyang Corporation discloses an amphiphilic diblock copolymer that is a slow-degradable drug delivery material, wherein the hydrophilic segment is PEG, and hydrophobic is PLA, PCL, PLGA, PLDO, poly(lactide-co-p-dioxanone), poly(orthoester), polyanhydride, poly(amino acid), and polycarbonate. However, the patent does not disclose that the copolymer is thermosensitive.
In U.S. Pat. No. 4,188,373, Krezanoski discloses an aqueous solution PEO-PPO polymer with a phase transfer temperature of 25° C. to 40° C., wherein the hydrogel system can be applied as a drug delivery carrier. However, the polymer material thereof has no hydrophobic segment.
In U.S. Pat. No. 4,474,752, Haslam discloses a medicine delivery system, wherein the medicine is liquid at room temperature and transforms to a semisolid or gel at body temperature. The hydrogel has 40-80% PEO and 20-60% PPO and a molecular weight of 7,000 to 50,000. However, the hydrogel does not have a hydrophobic segment.
In the Chem. Commun. 2001, 1516-1517, Jeong discloses a thermosensitive copolymer PLGA-g-PEG. The backbone of the polymer is PLGA and the side chains PEG are grafted on the backbone, wherein the lactide, glycolic acid, and PEG have a molar ratio of 3.2:1:2.8. The copolymer has a molecular weight of 9,300, a weight percent in water of 25 wt %, and a phase transfer temperature of 30° C. However, the paper fails to disclose that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid.
In the Polymer 2000, 41, 7091-7097, Lee discloses an amphiphilic polymer material with thermosensitivity. The polymer material is copolymerized of 2-ethyl-2-oxazoline and ε-caprolactone. However, the paper does not disclose that the hydrophobic segment is a random copolymer of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid.
In the Journal of Controlled Release 2002, 80, 69-77, Kim discloses a thermosensitive composite polymer hydrogel, wherein the hydrogel is photopolymerized of polyethylene oxide-polypropylene oxide and hyaluronic acid. The hydrogel serves as a human growth hormone delivery carrier to study drug release kinetics of related medicines and proteins. However, the polymer hydrogel does not have a hydrophobic segment.
In 1999, You Han Bae utilized condensation of PEG and PLA with carboxylic acid terminals to obtain a thermosensitive block copolymer PLA-PEG-PLA. The PEG has a molecular weight (Mn) of 1,000 to 2,000, and the PLA has a molecular weight of 820 to 3,150. The 1 wt % PLA-PEG-PLA aqueous solution has a low critical solution temperature (LCST) of 27° C. to 45° C., the aqueous solution does not transform into a gel or a semisolid, and the LCST is modified by tuning the length of the hydrophobic segment PLA. However, the thermosensitive polymer is not a diblock copolymer, and the hydrophobic segments thereof were not random copolymers of lactone or cyclic C3-C6 molecule and lactic acid/glycolic acid.